Assessment of Mitochondrial Respiration During Hypothermic Storage of Liver Biopsies Following Normothermic Machine Perfusion.

Organ quality can be assessed prior to transplantation, during normothermic machine perfusion (NMP) of the liver. Evaluation of mitochondrial function by high-resolution respirometry (HRR) may serve as a viability assessment concept in this setting. Freshly collected tissue is considered as optimal sample for HRR, but due to technical and personnel requirements, more flexible and schedulable measurements are needed. However, the impact of cold storage following NMP before processing biopsy samples for mitochondrial analysis remains unknown. We aimed at establishing an appropriate storage protocol of liver biopsies for HRR. Wedge biopsies of 5 human livers during NMP were obtained and assessed by HRR. Analysis was performed after 0, 4, 8, and 12 h of hypothermic storage (HTS) in HTK organ preservation solution at 4°C. With HTS up to 4 h, mitochondrial performance did not decrease in HTS samples compared with 0 h (OXPHOS, 44.62 [34.75-60.15] pmol·s-1·mg wet mass-1 vs. 43.73 [40.69-57.71], median [IQR], p > 0.999). However, at HTS beyond 4 h, mitochondrial respiration decreased. We conclude that HTS can be safely applied for extending the biopsy measurement window for up to 4 h to determine organ quality, but also that human liver respiration degrades beyond 4 h HTS following NMP.

The Predictive Value of Graft Viability and Bioenergetics Testing Towards the Outcome in Liver Transplantation.

Donor organ biomarkers with sufficient predictive value in liver transplantation (LT) are lacking. We herein evaluate liver viability and mitochondrial bioenergetics for their predictive capacity towards the outcome in LT. We enrolled 43 consecutive patients undergoing LT. Liver biopsy samples taken upon arrival after static cold storage were assessed by histology, real-time confocal imaging analysis (RTCA), and high-resolution respirometry (HRR) for mitochondrial respiration of tissue homogenates. Early allograft dysfunction (EAD) served as primary endpoint. HRR data were analysed with a focus on the efficacy of ATP production or P-L control efficiency, calculated as 1-L/P from the capacity of oxidative phosphorylation P and non-phosphorylating respiration L. Twenty-two recipients experienced EAD. Pre-transplant histology was not predictive of EAD. The mean RTCA score was significantly lower in the EAD cohort (-0.75 ± 2.27) compared to the IF cohort (0.70 ± 2.08; p = 0.01), indicating decreased cell viability. P-L control efficiency was predictive of EAD (0.76 ± 0.06 in IF vs. 0.70 ± 0.08 in EAD-livers; p = 0.02) and correlated with the RTCA score. Both RTCA and P-L control efficiency in biopsy samples taken during cold storage have predictive capacity towards the outcome in LT. Therefore, RTCA and HRR should be considered for risk stratification, viability assessment, and bioenergetic testing in liver transplantation.

The impact and relevance of techniques and fluids on lung injury in machine perfusion of lungs.

Primary graft dysfunction (PGD) is a common complication after lung transplantation. A plethora of contributing factors are known and assessment of donor lung function prior to organ retrieval is mandatory for determination of lung quality. Specialized centers increasingly perform ex vivo lung perfusion (EVLP) to further assess lung functionality and improve and extend lung preservation with the aim to increase lung utilization. EVLP can be performed following different protocols. The impact of the individual EVLP parameters on PGD development, organ function and postoperative outcome remains to be fully investigated. The variables relate to the engineering and function of the respective perfusion devices, such as the type of pump used, functional, like ventilation modes or physiological (e.g. perfusion solutions). This review reflects on the individual technical and fluid components relevant to EVLP and their respective impact on inflammatory response and outcome. We discuss key components of EVLP protocols and options for further improvement of EVLP in regard to PGD. This review offers an overview of available options for centers establishing an EVLP program and for researchers looking for ways to adapt existing protocols.

Mitochondrial respiration during normothermic liver machine perfusion predicts clinical outcome.

BACKGROUND: Reliable biomarkers for organ quality assessment during normothermic machine perfusion (NMP) are desired. ATP (adenosine triphosphate) production by oxidative phosphorylation plays a crucial role in the bioenergetic homeostasis of the liver. Thus, detailed analysis of the aerobic mitochondrial performance may serve as predictive tool towards the outcome after liver transplantation. METHODS: In a prospective clinical trial, 50 livers were subjected to NMP (OrganOx Metra) for up to 24.ßh. Biopsy and perfusate samples were collected at the end of cold storage, at 1.ßh, 6.ßh, end of NMP, and 1.ßh after reperfusion. Mitochondrial function and integrity were characterized by high-resolution respirometry (HRR), AMP, ADP, ATP and glutamate dehydrogenase analysis and correlated with the clinical outcome (L-GrAFT score). Real-time confocal microscopy was performed to assess tissue viability. Structural damage was investigated by histology, immunohistochemistry and transmission electron microscopy. FINDINGS: A considerable variability in tissue viability and mitochondrial respiration between individual livers at the end of cold storage was observed. During NMP, mitochondrial respiration with succinate and tissue viability remained stable. In the multivariate analysis of the 35 transplanted livers (15 were discarded), area under the curve (AUC) of LEAK respiration, cytochrome c control efficiency (mitochondrial outer membrane damage), and efficacy of the mitochondrial ATP production during the first 6.ßh of NMP correlated with L-GrAFT. INTERPRETATIONS: Bioenergetic competence during NMP plays a pivotal role in addition to tissue injury markers. The AUC for markers of outer mitochondrial membrane damage, ATP synthesis efficiency and dissipative respiration (LEAK) predict the clinical outcome upon liver transplantation. FUNDING: This study was funded by a Grant from the In Memoriam Dr. Gabriel Salzner Stiftung awarded to SS and the Tiroler Wissenschaftsfond granted to TH.

Cell-Based Regeneration and Treatment of Liver Diseases.

The liver, in combination with a functional biliary system, is responsible for maintaining a great number of vital body functions. However, acute and chronic liver diseases may lead to irreversible liver damage and, ultimately, liver failure. At the moment, the best curative option for patients suffering from end-stage liver disease is liver transplantation. However, the number of donor livers required by far surpasses the supply, leading to a significant organ shortage. Cellular therapies play an increasing role in the restoration of organ function and can be integrated into organ transplantation protocols. Different types and sources of stem cells are considered for this purpose, but highly specific immune cells are also the focus of attention when developing individualized therapies. In-depth knowledge of the underlying mechanisms governing cell differentiation and engraftment is crucial for clinical implementation. Additionally, novel technologies such as ex vivo machine perfusion and recent developments in tissue engineering may hold promising potential for the implementation of cell-based therapies to restore proper organ function.

Ex Vivo Mesenchymal Stem Cell Therapy to Regenerate Machine Perfused Organs.

Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine perfusion (NMP) has the potential to extend the donor pool by facilitating the use of marginal quality organs such as those from donors after cardiac death (DCD) and extended criteria donors (ECD). NMP provides a platform for organ quality assessment but also offers the opportunity to treat and eventually regenerate organs during the perfusion process prior to transplantation. Due to their anti-inflammatory, immunomodulatory and regenerative capacity, mesenchymal stem cells (MSCs) are considered as an interesting tool in this model system. Only a limited number of studies have reported on the use of MSCs during ex situ machine perfusion so far with a focus on feasibility and safety aspects. At this point, no clinical benefits have been conclusively demonstrated, and studies with controlled transplantation set-ups are urgently warranted to elucidate favorable effects of MSCs in order to improve organs during ex situ machine perfusion.

Distal Pancreatic Resection with Splenectomy in the Rat: A Pancreatic Fistula Model to Investigate Postsurgical Damage?

BACKGROUND: Postoperative pancreatic fistula (POPF) is a major complication in pancreatic surgery and can cause considerable postoperative morbidity. Advanced surgical-technical approaches to prevent POPF did not yield a substantial improvement. To investigate innovative treatments, experimental animal models of distal pancreatic resection and pancreaticoduodenectomy are of fundamental importance. After a failed attempt to replicate a previously described rat model for pancreatic fistula induction, we proceeded to distal pancreatic resection with splenectomy to provoke pancreatic leakage and generate a suitable animal model. METHODS: Distal pancreatic resection with splenectomy was performed in 40 rats. The rats were sacrificed on postoperative day (POD) 1, 2, 4, 6, 8, or 10, and the abdominal cavity was explored. Ascites probes were collected pre- and postoperatively for the detection of pancreas amylase and lipase. Tissue samples from the naïve pancreas (POD 0) and the postoperatively harvested remnant were evaluated histologically. The extent of necrosis was determined, and samples were examined for neutrophil infiltration. TUNEL staining served for the verification of necrosis in distinct cases. Immunohistochemistry of Ki67, von Willebrand factor, and CD68 was performed to evaluate proliferation, blood-vessel sprouting, and macrophage invasion. RESULTS: The rats showed no clinical symptoms or severe complications in the postoperative course up to 10 days. Abdominal exploration revealed adhesions in the upper abdomen, but no intra-abdominal fluid accumulations were found. Signs of inflammation and tissue damage were evident at the pancreatic resection margin on histological examination whereas the naïve pancreatic tissue was widely unaffected. Statistically significant differences were seen between the preoperative and postoperative extent of necrosis, the presence of neutrophil infiltrate, and levels of ascitic amylase and lipase. Immunohistochemical staining on Ki67, von Willebrand factor, and CD68 did not reveal any workable results on nonstatistical examination, and it was therefore not considered for further analyses. CONCLUSION: Creating a functional animal model of pancreatic fistula that reflects the clinical and pathophysiological impact of pancreatic leakage in humans has not been achieved. Our approach of left pancreatic resection recapitulated inflammation and tissue damage, early events in the development of fistulas, and it could be suitable for the experimental testing of novel targeting methods.

Myogenic progenitor cell transplantation for muscle regeneration following hindlimb ischemia and reperfusion.

BACKGROUND: Muscle is severely affected by ischemia/reperfusion injury (IRI). Quiescent satellite cells differentiating into myogenic progenitor cells (MPC) possess a remarkable regenerative potential. We herein established a model of local application of MPC in murine hindlimb ischemia/reperfusion to study cell engraftment and differentiation required for muscle regeneration. METHODS: A clamping model of murine (C57b/6 J) hindlimb ischemia was established to induce IRI in skeletal muscle. After 2 h (h) warm ischemic time (WIT) and reperfusion, reporter protein expressing MPC (TdTomato or Luci-GFP, 1 × 106 cells) obtained from isolated satellite cells were injected intramuscularly. Surface marker expression and differentiation potential of MPC were analyzed in vitro by flow cytometry and differentiation assay. In vivo bioluminescence imaging and histopathologic evaluation of biopsies were performed to quantify cell fate, engraftment and regeneration. RESULTS: 2h WIT induced severe IRI on muscle, and muscle fiber regeneration as per histopathology within 14 days after injury. Bioluminescence in vivo imaging demonstrated reporter protein signals of MPC in 2h WIT animals and controls over the study period (75 days). Bioluminescence signals were detected at the injection site and increased over time. TdTomato expressing MPC and myofibers were visible in host tissue on postoperative days 2 and 14, respectively, suggesting that injected MPC differentiated into muscle fibers. Higher reporter protein signals were found after 2h WIT compared to controls without ischemia, indicative for enhanced growth and/or engraftment of MPC injected into IRI-affected muscle antagonizing muscle damage caused by IRI. CONCLUSION: WIT-induced IRI in muscle requests increased numbers of injected MPC to engraft and persist, suggesting a possible rational for cell therapy to antagonize IRI. Further investigations are needed to evaluate the regenerative capacity and therapeutic advantage of MPC in the setting of ischemic limb injury.

Live Confocal Imaging as a Novel Tool to Assess Liver Quality: Insights From a Murine Model.

BACKGROUND: In an experimental murine liver clamping model, we aimed to investigate the efficacy of real-time confocal microscopy (RCM) in assessing viability of steatotic livers in comparison to standard assessment tools, including histopathological evaluation. METHODS: C57Bl/6 mice were subjected to a methionine-choline-deficient diet causing nonalcoholic fatty liver disease or to Lieber DeCarli diet causing ethanol-induced liver injury. Untreated animals served as controls. Liver biopsies were analyzed following challenge with 45 min of warm ischemia time and either 4 h of reperfusion or 24 h of cold storage. Organ quality assessment was performed at defined time points by RCM, histological staining, measurement of serum alanine aminotransferase activity, and expression analyses of proinflammatory cytokines. Additionally, survival analysis was performed. RESULTS: Cold as well as warm ischemia time resulted in a significant decrease in cell viability when compared with naive livers as well as nonischemic-challenged steatotic livers (P < 0.05) as assessed by RCM. Furthermore, RCM revealed the actual cellular damage at early time points, while established methods including H&E-staining and serum transaminase profile failed. CONCLUSIONS: In a translational attempt, we demonstrate that RCM is a suitable diagnostic tool to obtain information about functional damage of the liver apart from standard approaches.

Long-term outcome after hand and forearm transplantation - a retrospective study.

Between 2000 and 2014, five patients received bilateral hand (n = 3), bilateral forearm (n = 1), and unilateral hand (n = 1) transplants at the Innsbruck Medical University Hospital. We provide a comprehensive report of the long-term results at 20 years. During the 6-20 years follow-up, 43 rejection episodes were recorded in total. Of these, 27.9% were antibody-related with serum donor-specific alloantibodies (DSA) and skin-infiltrating B-cells. The cell phenotype in rejecting skin biopsies changed and C4d-staining increased with time post-transplantation. In the long-term, a change in hand appearance was observed. The functional outcome was highly depending on the level of amputation. The number and severity of rejections did not correlate with hand function, but negatively impacted on the patients´ well-being and quality of life. Patient satisfaction significantly correlated with upper limb function. One hand allograft eventually developed severe allograft vasculopathy and was amputated at 7 years. The patient later died due to progressive gastric cancer. The other four patients are currently rejection-free with moderate levels of immunosuppression. Hand transplantation remains a therapeutic option for carefully selected patients. A stable immunologic situation with optimized and individually adopted immunosuppression favors good compliance and patient satisfaction and may prevent development of DSA.

Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

Histomorphometric evaluation of ischemia-reperfusion injury and the effect of preservation solutions histidine-tryptophan-ketoglutarate and University of Wisconsin in limb transplantation.

BACKGROUND: The effect of cold ischemia (CI) in vascularized composite allotransplantation is unknown. We herein assess tissue-specific damage, acceptable CI time, and the effect of preservation solutions in a syngenic rat hindlimb transplant model. METHODS: Lewis rat limbs were flushed and stored for 2, 10, or 30 hr CI in saline, histidine-tryptophan-ketoglutarate or University of Wisconsin preservation solution before transplantation. Morphologic alterations, inflammation, and damage of the individual tissues were analyzed on day 10 using histomorphology, confocal, light, and transmission-electron microscopy. RESULTS: Two-hour CI led to mild inflammation of tissues on day 10, whereas 10-hr and 30-hr CI resulted in massive inflammation and tissue damage. Although muscle was mainly affected after prolonged CI (≥10 hr), nerve was affected in all CI groups. A perineural cell infiltrate, hypercellular appearance, pronounced vacuolization, and mucoid degeneration, appearing as Wallerian degeneration, were observed. Staining with propidium iodide and Syto 16 revealed a decrease in viable muscle cell nuclei in the anterior tibial muscle on day 10 in all groups, which was most pronounced in 10-hr and 30-hr CI animals. Transmission-electron microscopy indicated that a large number of mitochondria were degenerated in the 10-hr and 30-hr CI groups. Histidine-tryptophan-ketoglutarate preservation solution slightly decreased inflammation and tissue damage compared to University of Wisconsin-treated and saline-treated animals, especially in skin and muscle when CI times did not exceed 10 hr. CONCLUSION: Severe inflammation and tissue damage are observed after prolonged CI in muscle and nerve. Ischemia times in vascularized composite allotransplantation should be kept as short as possible and certainly below 10 hr.

Insights from computational modeling in inflammation and acute rejection in limb transplantation.

Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1ß, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection.

Lymphoid neogenesis in skin of human hand, nonhuman primate, and rat vascularized composite allografts.

The mechanisms of skin rejection in vascularized composite allotransplantation (VCA) remain incompletely understood. The formation of tertiary lymphoid organs (TLO) in hand transplantation has been recently described. We assess this phenomenon in experimental and clinical VCA rejection. Skin biopsies of human (n = 187), nonhuman primate (n = 11), and rat (n = 15) VCAs were analyzed for presence of TLO. A comprehensive immunohistochemical assessment (characterization of the cell infiltrate, expression of adhesion molecules) including staining for peripheral node addressin (PNAd) was performed and correlated with rejection and time post-transplantation. TLO were identified in human, nonhuman primate, and rat skin samples. Expression of PNAd was increased in the endothelium of vessels upon rejection in human skin (P = 0.003) and correlated with B- and T-lymphocyte numbers and LFA-1 expression. PNAd expression was observed at all time-points after transplantation and increased significantly after year 5. In nonhuman primate skin, PNAd expression was found during inflammatory conditions early and late after transplantation. In rat skin, PNAd expression was strongly associated with acute rejection and time post-transplantation. Lymphoid neogenesis and TLO formation can be uniformly found in experimental and human VCA. PNAd expression in vascular endothelium correlates with skin rejection and T- and B-cell infiltration.

Vascularized composite allografts and solid organ transplants: similarities and differences.

PURPOSE OF REVIEW: Vascularized composite allotransplantation (VCA) is a treatment for complex tissue injuries and defects of extremities and face. During the past thirteen years, more than 100 VCA cases have been reported. Form and function restored with VCA have exceeded the results achieved with conventional surgical techniques. The review summarized the development in VCA over the past 12 months with references of and comparison with solid organ transplantation. RECENT FINDINGS: The highlights reported in the latest publications included a better understanding of topical immunosuppressants for prevention and treatment of VCA rejection, mechanisms of chronic rejection and minimization of immunosuppressive maintenance treatment using a cell-based protocol in human upper-extremity transplantation. SUMMARY: We herein summarize the progress made in VCA in the last year with a focus on new clinical immunosuppressive strategies and novel targets for immunosuppression and immunomodulation including the application of mesenchymal stem cells for transplant tolerance.

Standardizing skin biopsy sampling to assess rejection in vascularized composite allotransplantation.

Over 70 hands and 20 faces have been transplanted during the past 13 yr, which have shown good to excellent functional and esthetic outcomes. However, (skin) rejection episodes complicate the post-operative courses of hand and face transplant recipients and are still a major obstacle to overcome after reconstructive allotransplantation. This article summarizes all relevant information on the skin component and rejection of a vascularized composite allograft. As more and more centers plan to implement a vascularized composite allotransplantation (VCA) program, we further develop guidelines and recommendations on collection and processing of skin biopsies from hand and face allograft recipients. This will help to standardize post-operative monitoring, avoid pitfalls for those new in the field and facilitate comparison of data on VCA between centers.

The psychological assessment of candidates for reconstructive hand transplantation.

Standardized psychological assessment of candidates for reconstructive hand transplantation (RHT) is a new approach in transplantation medicine. Currently, international guidelines and standardized criteria for the evaluation are not established. Patients suffering from the loss of a hand or an upper extremity have to cope with multiple challenges. For a selected group of patients, RHT represents an option for restoring natural function and for regaining daily living independence. The identification of at-risk patients and those requiring ongoing counseling due to poor coping or limited psychological resources are the primary focus of the psychological assessment. We have developed the 'Innsbruck Psychological Screening Program for Reconstructive Transplantation (iRT-PSP)' which utilizes a semi-structured interview and standardized psychological screening procedures and continuous follow-up ratings. Between January 2011 and October 2011, four candidates were evaluated using the iRT-PSP. Psychological impairments including social withdrawal, embarrassment, reduced self-esteem, and a depressive coping style were identified and poor quality of life was reported. The motivation for transplantation was diverse, depending on many factors such as bi- or unilateral impairment, native or accidental loss of hand, and social integration.

Outcomes with respect to disabilities of the upper limb after hand allograft transplantation: a systematic review.

The aim of this work is to compare disabilities of the upper limb before and after hand allograft transplantation (HAT), and to describe the side effects of immunosuppressive (IS) agents given to recipients of hand allografts. Clinical cases of HAT published between 1999 and 2011 in English, French, or German were reviewed systematically, with emphasis on comparing disabilities of the arm, shoulder and hand (DASH) scores before and after transplantation. Duration of ischemia, extent of amputation, and time since amputation were evaluated for their effect on intrinsic musculature function. Infectious, metabolic, and oncological complications because of IS therapy were recorded. Twenty-eight patients were reported in 56 clinical manuscripts. Among these patients, disabilities of the upper limb dropped by a mean of 27.6 (±19.04) points on the DASH score after HAT (P = 0.005). Lower DASH scores (P = 0.036) were recorded after secondary surgery on hand allografts. The presence of intrinsic muscle function was observed in 57% of the recipients. Duration of ischemia, extent of transplantation, and time since amputation were not associated statistically with the return of intrinsic musculature function. Three grafts were lost to follow-up because of noncompliance with immunosuppression, rejection, and arterial thrombosis, respectively. Fifty-two complications caused by IS agents were reported, and they were successfully managed medically or surgically. HAT recipients showed notable functional gains, but most complications resulted from the IS protocols.

Histopathologic characterization of mild rejection (grade I) in skin biopsies of human hand allografts.

Mild skin rejection is a common observation in reconstructive transplantation. To enlighten the role of this inflammatory reaction we investigated markers for cellular and antibody mediated rejection, adhesion molecules and tolerance markers. Forty-seven skin biopsies (rejection grade I) of human hand allografts were investigated by immunohistochemistry (CD3, CD4, CD8, CD20, CD68, C4d, LFA-1, ICAM-1, E-selectin, P-selectin, VE-cadherin, HLA-DR, IDO, and Foxp3). Expression was read with respect to time after transplant. The infiltrate was mainly comprised of CD3+T-lymphocytes. Among these, CD8+cells were more prominent than CD4+cells. CD20+B-lymphocytes were sparse and CD68+macrophages were found in some, but not all samples (approximately 10% of the infiltrate). The CD4/CD8-ratio was increased after the first year. C4d staining was mainly positive in samples at time-points later than 1 year. Adhesion molecules LFA-1, ICAM-1, E-selectin, P-selectin, and VE-cadherin were found upregulated, and for P-selectin, expression increased with time after transplant. IDO expression was strongest at 3 months-1 year post-transplant and a tendency toward more Foxp3+ cells at later time points was observed. Mild skin rejection after hand transplantation presents with a T-cell dominated dermal cell infiltrate and upregulation of adhesion molecules. The role of C4d expression after year one remains to be elucidated.

World experience after more than a decade of clinical hand transplantation: update on the Innsbruck program.

Patients who have lost a hand or upper extremity face many challenges in everyday life. For some patients, reconstructive hand transplantation represents a reasonable option for anatomic reconstruction, restoring prehensile function with sensation and allowing them to regain daily living independence. The first clinical case of bilateral hand transplantation at University Hospital Innsbruck was realized on March 17th, 2000. A decade later, a total of 7 hands and forearms were transplanted in 4 patients. This article review the clinical courses of 3 bilateral hand transplant recipients and highlights psychological aspects on reconstructive hand transplantation with special regard to unilateral/bilateral transplantation.